Adult trkB signaling in parvalbumin interneurons is essential to prefrontal network dynamics

Inhibitory interneurons expressing parvalbumin (PV) are central to cortical network dynamics, generation of c oscillations, and cognition. Dysfunction of PV interneurons disrupts cortical information processing and cognitive behavior. Brain-derived neurotrophic factor (BDNF)/tyrosine receptor kinase B (trkB) signaling regulates the maturation of cortical PV interneurons but is also implicated in their adult multidimensional functions. Using a novel viral strategy for cell-type-specific and spatially restricted expression of a dominant-negative trkB (trkB.DN), we show that BDNF/trkB signaling is essential to the integrity and maintenance of prefrontal PV interneurons in adult male and female mice. Reduced BDNF/trkB signaling in PV interneurons in the medial prefrontal cortex (mPFC) resulted in deficient PV inhibition and increased baseline local field potential (LFP) activity in a broad frequency band. The altered network activity was particularly pronounced during increased activation of the prefrontal network and was associated with changed dynamics of local excitatory neurons, as well as decreased modulation of the LFP, abnormalities that appeared to generalize across stimuli and brain states. In addition, our findings link reduced BDNF/trkB signaling in prefrontal PV interneurons to increased aggression. Together our investigations demonstrate that BDNF/trkB signaling in PV interneurons in the adult mPFC is essential to local network dynamics and cognitive behavior. Our data provide direct support for the suggested association between decreased trkB signaling, deficient PV inhibition, and altered prefrontal circuitry.ERCSwedish Research CouncilCAPES-STINT Program GrantKarolinska InstitutetKnut and Alice Wallenberg FoundationSTINT Program Joint Brazilian-Swedish Research Collaboration GrantPublishe

Inhibition in cognition : neurophysiology and connectivity of gabaergic interneurons in the prefrontal cortex

The prefrontal cortex (PFC) is a cortical region involved in higher-order cognitive functions, it is widely connected to the rest of the neocortex and is involved in tasks that require temporal integration of information. The local PFC circuit contains excitatory pyramidal neurons and inhibitory interneurons, and the interplay between these is essential for computations in the PFC. Parvalbumin (PV) expressing interneurons form a subclass of inhibitory interneurons in the neocortex. PV interneurons are fast spiking interneurons that can control the output of pyramidal neurons. PV interneurons play an important role in maintaining the excitatory/inhibitory balance in the PFC. The PFC, and specifically PV interneurons in the PFC, play an important role in several mental disorders. This thesis explores the input to excitatory and inhibitory neurons in the PFC, and investigates the local connectivity between these neurons. Study I revealed a whole-brain atlas of inputs to four types of neurons in the PFC. All four neuron types receive similar inputs from the rest of the brain. The connections between local interneurons were also investigated and revealed varying degrees of connectivity between different subtypes. Study II focused on generating a PV-Cre rat and demonstrated that PV interneurons in the rat could be reliably targeted both ex vivo and in vivo. Study III centred around the effect of PV interneurons on BDNF/trkB signaling and how this altered the local PFC circuit. Following overexpressing of a truncated trkB receptor, BDNF/trkB signaling is impaired; this decreased PV inhibition, altered the LFP and was linked to increased aggression in mice. Study IV investigated the connection from the auditory cortex to the PFC and showed that both pyramidal neurons and PV interneurons receive monosynaptic, excitatory input from the auditory cortex. This thesis sheds light on the inputs to the PFC and in particular on prefrontal PV interneurons. Furthermore, it shows that BDNF/trkB signalling in PV interneurons is important for PFC function and it elucidates the local connectivity patterns in the PFC

Cell-type-specific representation of spatial context in the rat prefrontal cortex

Summary: The ability to represent one’s own position in relation to cues, goals, or threats is crucial to successful goal-directed behavior. Using optotagging in knock-in rats expressing Cre recombinase in parvalbumin (PV) neurons (PV-Cre rats), we demonstrate cell-type-specific encoding of spatial and movement variables in the medial prefrontal cortex (mPFC) during goal-directed reward seeking. Single neurons encoded the conjunction of the animal’s spatial position and the run direction, referred to as the spatial context. The spatial context was most prominently represented by the inhibitory PV interneurons. Movement toward the reward was signified by increased local field potential (LFP) oscillations in the gamma band but this LFP signature was not related to the spatial information in the neuronal firing. The results highlight how spatial information is incorporated into cognitive operations in the mPFC. The presented PV-Cre line opens the door for expanded research approaches in rats

Robust derivation of transplantable dopamine neurons from human pluripotent stem cells by timed retinoic acid delivery

Stem cell therapies for Parkinson’s disease (PD) have entered first-in-human clinical trials using a set of technically related methods to produce mesencephalic dopamine (mDA) neurons from human pluripotent stem cells (hPSCs). Here, we outline an approach for high-yield derivation of mDA neurons that principally differs from alternative technologies by utilizing retinoic acid (RA) signaling, instead of WNT and FGF8 signaling, to specify mesencephalic fate. Unlike most morphogen signals, where precise concentration determines cell fate, it is the duration of RA exposure that is the key-parameter for mesencephalic specification. This concentration-insensitive patterning approach provides robustness and reduces the need for protocol-adjustments between hPSC-lines. RA-specified progenitors promptly differentiate into functional mDA neurons in vitro, and successfully engraft and relieve motor deficits after transplantation in a rat PD model. Our study provides a potential alternative route for cell therapy and disease modelling that due to its robustness could be particularly expedient when use of autologous- or immunologically matched cells is considered